PROJECT SUMMARY/ABSTRACT Management of liver failure after resection or drug injury and prevention and treatment of liver tumors is a major medical challenge to the VA population. Understanding mechanisms of liver regeneration will provide a profound strategy to meet this challenge. Liver regeneration is a well-orchestrated process. Portal circulation and gut-derived factors are critical to liver functions. However, the nature of the factor(s) present in portal blood to promote liver regeneration is unclear and identifying these factors will provide novel strategies to treat liver diseases. An endocrine fibroblast growth factor, FGF15 /19 (15 in mice and 19 in humans), is critical in regulating liver functions as it is known to suppress bile acid synthesis by activating its receptor on hepatocytes, fibroblast growth factor receptor 4 (FGFR4). FGF15/19 is mainly produced in the ileum following activation of the farnesoid X receptor (FXR). Recently, studies from our and other groups have shown that FGF15/19 emerges to be gut-derived mitogens for hepatocyte proliferation due to its suppressive effect on bile acid synthesis and by direct stimulation of cell proliferation. The purpose of the current application is to determine the underlying molecular mechanism by which the intestine-derived FGF15/19 directly promotes cell proliferation and liver regeneration. Our compelling published and preliminary data suggest that FGF15 is important in liver regeneration. We have formulated a novel hypothesis that a major mechanisms by which FGF15 promotes liver regeneration is by direct activation of critical early signaling pathways (MAPK, STAT3 and NF?B) in cell proliferation (Fig 1). This hypothesis will be tested in three independent but related specific aims: Specific Aim 1: fully characterize the cell proliferative effects of FGF15/19 in vitro and in vivo. Specific Aim 2: Determine the molecular mechanism by which FGF15 regulates hepatocyte proliferation and liver regeneration. Specific Aim 3: determine the functional domains/sequences of FGF15/19 protein in promoting cell proliferation and in suppressing bile acid synthesis. The working hypothesis is that certain amino acid sequence within the FGF15 and FGF19 protein is responsible for differential effects (cell proliferation vs. suppression of bile acid synthesis). We will determine the FGF15 protein sequence or domains critical in promoting cell proliferation versus suppression of bile acid synthesis, with a direct comparison of FGF19. This aim will provide scientific insight to modify FGF19 in differential treatment of liver diseases in the future. This project is innovative both conceptually and in the implementation of experimental approaches by establishing a gut regulatory pathway mediated by FGF15/19 in hepatocyte proliferation and liver regeneration. This will improve the management of liver failure after surgical resection, chemical exposure or behavioral disruptions, as well as in the prevention and treatment of liver tumor.